Caspofungin

Caspofungin
Systematic (IUPAC) name
(10R,12S)-N-{(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-aminoethyl)amino]-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2',1'-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl}-10,12-dimethyltetradecanamide
Clinical data
Trade names Cancidas
AHFS/Drugs.com monograph
License data
Pregnancy
category
  • C
Routes of
administration

IV

<--Pharmacokinetic data-->
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (intravenous use only)
Protein binding 97%
Biological half-life

9–11 hours

<--Identifiers-->
Identifiers
CAS Number 179463-17-3 YesY
ATC code J02AX04 (WHO)
PubChem CID 468682
DrugBank DB00520 YesY
ChemSpider 13180298 YesY
UNII VUW370O5QE N
ChEBI CHEBI:474180
ChEMBL

[https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL499808 <--Chemical data--> CHEMBL499808

<--Chemical data-->] N
Chemical data
Formula C52H88N10O15
Molar mass 1093.31 g/mol
 NYesY (what is this?)  (verify)

Caspofungin (INN)[1] (brand name Cancidas worldwide) is a lipopeptide antifungal drug from Merck & Co., Inc. discovered by James Balkovec, Regina Black and Frances A. Bouffard.[2] It is a member of a new class of antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby disturbing the integrity of the fungal cell wall. Caspofungin was the first inhibitor of fungal (1→3)-β-D-glucan synthesis to be approved by the United States Food and Drug Administration.[3] Caspofungin is administered intravenously.

Spectrum of fungal susceptibility and resistance

Caspofungin has been effective in treating fungal infections caused by Aspergillus and Candida species. The following represents MIC susceptibility for a few medically significant organisms.[4]

Indications

Caspofungin acetate for injection was originally approved by both the Food and Drug Administration (FDA), in the U.S., and the EMEA, in Europe, in 2001.

Its currently approved therapeutic indications by both organisations include the empirical therapy of presumed fungal infections in febrile, neutropenic adult patients and the treatment of invasive aspergillosis in adult patients whose disease is refractory to, or who are intolerant of, other antifungal agents (i.e., conventional or lipid formulations of amphotericin B and/or itraconazole). Additionally, the FDA approval includes indication for the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, peritonitis, pleural cavity infections, and esophagitis) and the EMEA approval includes indication for the treatment of general invasive candidiasis in adult patients.

Clinical efficacy

About 36% of patients refractory to other therapies responded well to caspofungin therapy, while even 70% of patients intolerant to other therapies were classified as responders. Direct comparative studies to other drugs in the treatment of invasive aspergillosis have so far not been undertaken.

Contraindications

Known hypersensitivity to caspofungin acetate or any other ingredient contained in the formulation contraindicate its use.

Warnings

The concomitant use of caspofungin and cyclosporine in healthy volunteers led to a more frequent increase of liver enzymes (ALT=SGPT and AST=SGOT) than noted with cyclosporine alone. Combination treatment is only indicated if the potential benefit for the patient outweighs the potential risk.

Dosage reduction in patients with moderately impaired liver function is recommended. No clinical data exist regarding the use of caspofungin in patients with severely impaired liver function.

Reactions due to histamine release (rash, facial swelling, pruritus, sensation of warmth and one case of anaphylaxis) have been seen. Health-care providers should carefully watch for these reactions.

In a few patients with infections caused by Candida albicans, mutants with reduced sensitivity to caspofungin have been noticed. Currently there are no data regarding development of resistance in other fungi than C. albicans.

Pregnancy and lactation

Caspofungin has been shown in animal studies to have embroyotoxic properties, and therefore has been assigned to class C. It should only be given to pregnant women if the benefit to the mother clearly outweighs the potential risk to her fetus.

The drug is found in the milk of lactating rats, but it is not known whether this is seen in humans. Thus, lactating women should be treated cautiously.

Geriatric patients

Ordinarily, no dose adjustments are necessary.

Pediatric patients

Caspofungin is FDA approved for pediatric patients 3 months and older. Dosing is based on body surface area (BSA) as calculated by the Mosteller formula.[5]

Side effects

Compared to amphotericin B, caspofungin seems to have a relatively low incidence of side effects. In clinical studies and postmarketing reports, the side effects seen in 1% or more of the patients were as follows:

Additionally, infrequent cases of symptomatic liver damage, peripheral edema and swelling, and hypercalcemia have been seen. One case of anaphylaxis (severe allergic reaction) has also been noted.

Resistance

Resistance in C. albicans has been described, but is currently still rare. The mechanism is probably a point mutation in the (1→3)-β-D-glucan synthase gene.[6]

Drug interactions

Duration of treatment

The mean duration of therapy in previous studies was 34 days. Some patients were even healed by a one-day treatment. However, a few patients were treated for as long as 162 days and tolerated the drug well, indicating that longtime use may be indicated and tolerated favourably in complicated cases of aspergillosis. Generally, the duration of treatment is dictated by the severity of the disease, the clinical response, and the improvement of immunocompetence in immunocompromised patients.

Dosage

An initial dose of 70 mg by intravenous infusion is given followed by 50 mg intravenous daily. If no response is seen or if inducers of caspofungin clearance (see above) are coadministered the daily dose may be increased to 70 mg. An infusion should take approximately 1 hour.

Dosage forms

Semisynthesis

Caspofungin is semisynthesized from pneumocandin B0, a fermentation product of Glarea lozoyensis.[3]

References

  1. ↑ European Medicines Agency's list of authorised medicines for human use (C)
  2. ↑ "Patent Covering Caspofungin". https://www.google.com/patents/US5378804?dq=5378804&hl=en&sa=X&ei=pHIJVZntI4uWNpStg6gK&ved=0CB0Q6AEwAA. External link in |website= (help);
  3. 1 2 Deresinski SC; Stevens DA (2003). "Caspofungin". Clin Infect Dis 36 (11): 1445–1457. doi:10.1086/375080. PMID 12766841.
  4. ↑ http://www.toku-e.com/Assets/MIC/Caspofungin%20acetate.pdf
  5. ↑ Mosteller RD. "Simplified calculation of body-surface area". N Engl J Med 1987; 317:1098. PMID 3657876.
  6. ↑ Baixench M; Aoun N; Desnos-Ollivier M; et al. (2007). "Acquired resistance to echinocandins in Candida albicans: case report and review". Journal of Antimicrobial Chemotherapy 59 (6): 1076–1083. doi:10.1093/jac/dkm095. PMID 17468115.

External links

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